Process for the preparation of substituted phenylpropanones

ABSTRACT

The invention relates to a process for the preparation of a compound of formula (I) wherein the substituents are defined as in claim  1,  which process comprises adding a compound of formula (II), wherein R 1 , R 2  and R 3  have the meanings as described under formula (I), in the presence of an inert organic solvent, to a mixture comprising an organic nitrite of formula (III) R4—O—N═O, wherein R 4  is C 1 -C 8 alkyl, a compound of formula (IV), and an inert organic solvent.

The present invention relates to a process for the preparation ofpropane-2-one-substituted phenyls, in particular to the preparation of1-(2,4,6-trihalo-phenyl)-propan-2-ones.

Propane-2-one-substituted phenyls are valuable intermediates for thepreparation of fungicidally active pyrazole carboxamides, as describedfor example in WO 2010/063700.

It is known from scheme 3 on page 11 of WO 2010/063700 to preparepropane-2-one-substituted phenyls by

a) reducing a compound of formula XIX to a compound of formula XX,

wherein R₁₁ is hydrogen, halogen or C₁-C₆alkyl;

R₁₂ is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆alkinyl,C₃-C₆cycloalkyl-C₃-C₆alkinyl, halophenoxy, halophenyl-C₃-C₆alkinyl,C(C₁-C₄alkyl)═NO—C₁-C₄alkyl, C₁-C₆haloalkyl,

C₁-C₆haloalkoxy, C₂-C₆haloalkenyl, or C₂-C₆haloalkenyloxy; and

R₁₃ is hydrogen, halogen or C₁-C₆alkyl;

b) reacting the compound of formula XX to an activated benzylicderivative of formula XXI,

wherein Y represents a leaving group, such as halogen, mesylate ortosylate,

c) reacting the compound of formula XXI to the nitril derivative offormula XXII

and

d) reacting the compound of formula XXII with a Grignard reagent of theformula R₅-MgBr, wherein R₅ is for example methyl, to thepropane-2-one-substituted phenyl of formula Xa (wherein R₅ is methyl).

A disadvantage of this prior art process is the high production costscaused by the significant number of reaction steps which makes thisprocess uneconomical and especially unsuitable for a large-scaleproduction.

WO 00/34229 describes a process for the preparation of a ketone offormula V

by diazotizing an aniline of formula VI

and reacting the resulting diazonium salt with isopropenylacetate offormula X

and reacting the resulting ketone of formula XI

with an organic nitrite in the presence of hydrogen chloride.

A disadvantage of this process is the accumulation of the very reactivediazonium salt in the reaction mixture. Diazonium salts in general aresensitive to physical agents such as heat, light, shock, staticelectricity and dehydration that can lead to rapid, uncontrollabledecompositions and explosions.

A further disadvantage is that 2 different equipments are needed toperform the reactions.

The aim of the present invention is therefore to provide a novel processfor the production of

propane-2-one-substituted phenyls that avoids the disadvantages of theknown process and makes it possible to prepare propane-2-one-substitutedphenyls in high yields and good quality in an economically advantageousway with less reaction steps.

Thus, according to the present invention, there is provided a processfor the preparation of the compound of formula I

wherein

R₁ is hydrogen, halogen or C₁-C₆alkyl;

R₂ is hydrogen, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆alkinyl,C₃-C₆cycloalkyl-C₃-C₆alkinyl, halophenoxy, halophenyl-C₃-C₆alkinyl,C(C₁-₄alkyl)═NO—C₁-C₄alkyl, C₁-C₆haloalkyl,

C₁-C₆haloalkoxy, C₂-C₆haloalkenyl or C₂-C₆haloalkenyloxy; and

R₃ is hydrogen, halogen or C₁-C₆alkyl;

which process comprises

adding a compound of formula II

wherein R₁, R₂ and R₃ have the meanings as described under formula I, inthe presence of an inert organic solvent, to a mixture comprising anorganic nitrite of formula III

R₄—O—N═O   (III),

wherein R₄ is C₁-C₈alkyl, a compound of formula IV

and an inert organic solvent.

The process according to the invention uses easily accessible andnontoxic starting material, without the need of isolation oraccumulation of diazonium salt and is therefore especially suitable forthe large-scale preparation of a compound of formula I.

The process according to the invention is especially suitable for theproduction of compounds of formula I, wherein at least one of R₁, R₂ andR₃ is different from hydrogen. The process according to the invention isespecially suitable for the preparation of compounds of formula I,wherein at least one of R₁, R₂ and R₃ is halogen.

Further compounds of formula I can be advantageously prepared, whereinR₁, R₂ and R₃ are all halogen, especially chloro. Compounds of formula Iwhich can be advantageously prepared according to the process of thisinvention are described in Table 1.

TABLE 1 Preferred compounds of formula I (I)

No. R₁ R₂ R₃ 1.01 Cl Cl Cl 1.02 Cl H Cl 1.03 Cl Cl H 1.04 Cl Br Cl 1.05Br Br Br 1.06 H Cl H 1.07 H Br H 1.08 H CF₃ H

The compound of formula V can be prepared preferably by a one potreaction adding the aniline of formula II to a mixture ofisoprenylacetate of formula IV, an organic nitrite of formula III and asolvent. In preferred compounds of formula III, R₄ is C₄-C₇alkyl. Apreferred nitrite is tert-butyl nitrite.

The mixture of isoprenylacetate of formula IV, an organic nitrite offormula III and a solvent can additionally contain a copper compoundwhich can be advantageous to increase yield and/or quality of theproduct. Preferred copper compounds are CuO, CuCl₂ or CuSO₄. The amountof the copper compounds is preferably is 1-20 mol % in the relation tothe aniline of formula II. Advantageous for the reaction is atemperature of −10° C. to 50° C. No isolation or accumulation of thediazonium salt is required for this process step. Preferably, the samesolvent is used for the aniline of formula II and the mixture ofisoprenylacetate of formula IV, and the organic nitrite of formula III.Suitable inert organic solvents are for example ketones, for exampleacetone, methylethylketone (MEK) or nitriles, for example acetonitrile.Preferred solvents are acetone and acetonitrile.

The compounds of formula II and III are either known or can be preparedaccording to methods well known in the art. Some compounds of formula IIare commercially available, e.g. the compound of formula II, wherein R₁,R₂ and R₃ is chloro. Isoprenylacetate of formula IV is commerciallyavailable.

PREPARATORY EXAMPLES Example P1 Preparation of1-(2,4,6-trichloro-phenyl)-propan-2-one (Compound CAS1228284-86-3)

In a 1.5 l sulfonation flask equipped with mechanical stirring, coolingfunnel, dropping funnel and thermometer under nitrogen at ambienttemperature filled with acetone (240 ml), were added isopropenyl acetate(66 ml, 0.60 mol), tert-butyl nitrite (40 ml, 0.30 mol) and cupricsulfate pentahydrate (2.5 g, 0.001 mol) . The resulting light green-bluesuspension is stirred for 15 min at ambient temperature. A solution of2,4,6-trichloroaniline (40 g, 0.20 mol), dissolved in acetone (320 ml)was added dropwise over a period of 2 hours. During the addition,bubbling observed, temperature rose to 30° C. and the mixture turnedgreen. 1 Hour after the addition, an amber solution was obtained. Themixture was stirred for 6 hours. Completion of the reaction wasconfirmed by GC-MS. The crude mixture was concentrated under reducepressure to remove most of the acetone and the residue was dissolved inethyl acetate (300 ml) and wash with 1M hydrochloric acid (2×300 ml),water (2×300 ml) potassium carbonate solution (300 ml) followed by water(300 ml). Combined basic aqueous were re-extracted with of ethyl acetate(150 ml). Combined organics were dried over sodium sulfate, and theorganics were concentrated under reduced pressure to give crude1-(2,4,6-trichloro-phenyl)-propan-2-one (53 g) as a dark brown oil. Thecrude was dissolved again in ethyl acetate (200 ml) and washed with 1Msodium hydroxide (300 ml) 1M hydrochloric acid (100 ml) and water (200ml). The organic layers were dried and evaporated to give crude1-(2,4,6-trichloro-phenyl)-propan-2-one 49 g dark brown oil whichcrystallized.

¹H NMR (400 MHz, CDCl₃): δ 2.26 (s,3H,CH₃), 4.05(s,2H,CH₂), 7.34 (s,2H,Ar-H)

Example P2 Preparation of 1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one

In a 50 ml three-neck flask equipped with mechanical stirring, coolingfunnel, dropping funnel and thermometer under nitrogen at ambienttemperature filled with acetonitrile (10 ml), were added cuprous oxide(1.5 g, 0.018 mol), isopropenyl acetate (13.6 ml, 0.125 mol) andtert-butyl nitrite (1.7 ml, 0.0125 mol). The resulting red suspension isstirred for 15 min at ambient temperature. A solution of4-bromo-2,6-dichloroaniline (2.0 g, 0.0083 mol), dissolved inacetonitrile (15 ml) was added dropwise over a period of 20 minutes.During the addition, bubbling was observed. The mixture was stirred at40° C. for 20 hours. The red crude mixture was passed through celite toremove solid particles and concentrated under reduce pressure to give abrown solid. The residue was dissolved in dichloromethane (120 ml) andwashed with water (2×50 ml) and brine (40 ml). Organics were dried oversodium sulfate and concentrated under reduced pressure to give crude1-(4-bromo-2,6-dichloro-phenyl)-propan-2-one (2.3g) as a dark brown oil.

¹H NMR (400 MHz, CDCl₃): δ 2.25 (s,3H,CH₃), 4.06(s,2H,CH₂), 7.50 (s,2H,Ar-H)

Example P3 Preparation of 1-(2,4,6-trichloro-phenyl)-propan-2-one

A mixture of isopropenyl acetate (12.2 g, 122 mmol),2,4,6-trichloroaniline (16.0 g, 81.4 mmol), potassium carbonate (100 mg,0.7 mmol), and acetone (100 g) was cooled to 10° C. tert-Butyl nitrite(90%, 10 g, 87.3 mmol) was dosed over 30 minutes. The reaction wasstirred for further 90 minutes, and it was concentrated to a black oil.The residue was triturated with water, and the pH was adjusted to 10.5with sodium hydroxide solution. The precipitate was filtered andrecrystallized from methanol-water 1:1. The solid was filtered, washedwith methanol-water 1:1, and dried. The product was obtained asdark-brown crystalline material (15.9 g, 70.7% purity, 47.3 mmol, 58%yield). Further purification was achieved by recrystallization fromhexanes. 1H NMR (400 MHz, CDCI₃): δ 2.23 (s, 3H, CH₃), 4.02 (s, 2H,CH₂), 7.31 (s, 2H, CH).

What is claimed is:
 1. A process for the preparation of the compound offormula I

wherein R₁ is hydrogen, halogen or C₁-C₆alkyl; R₂ is hydrogen, halogen,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆alkinyl, C₃-C₆cycloalkyl-C₃-C₆alkinyl,halophenoxy, halophenyl-C₃-C₆alkinyl, C(C₁-C₄alkyl)═NO—C₁-C₄alkyl,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₂-C₆haloalkenyl, orC₂-C₆haloalkenyloxy; R₃ is hydrogen, halogen, C₁-C₆alkyl; which processcomprises adding a compound of formula II

wherein R₁, R₂ and R₃ have the meanings as described under formula I, inthe presence of an inert organic solvent to a mixture comprising anorganic nitrite of formula IIIR₄—O—N═O   (III), wherein R₄ is C₁-C₈alkyl, a compound of formula IV

and an inert organic solvent.
 2. A process according to claim 1 for thepreparation of a compound of formula I, wherein at least one of R₁, R₂and R₃ is different from hydrogen.
 3. A process according to claim 1 forthe preparation of a compound of formula I, wherein at least one of R₁,R₂ and R₃ is halogen.
 4. A process according to claim 1 for thepreparation of a compound of formula I, wherein R₁, R₂ and R₃ arechloro.
 5. A process according to claim 1 for the preparation of acompound of formula I, wherein R is C₄-C₇alkyl.